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See detailNew Improvements in the Enantioselective Synthesis of 2-[18F]Fluoro-L-Tyrosine and 6-[18F]Fluoro-L-Dopa
Libert, Lionel ULg; Lemaire, Christian ULg; Denoël, Thibaut ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 196

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See detailAre Ionic Liquid Useful for Fluorine-18 Labeling?
Aerts, Joël ULg; Lemaire, Christian ULg; Plenevaux, Alain ULg et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 193

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See detailUse of Organic Bases for 18F-Fluoride Anion Exchange Elution avoiding the Classical Azeotropic drying Step Before Labeling
Lemaire, Christian ULg; Aerts, Joël ULg; Voccia, Samuel et al

in Journal of Labelled Compounds & Radiopharmaceuticals (2009, July), 52(S1), 198

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See detailMultivariate analysis of cognitive profiles in Alzheimer's disease
Bastin, Christine ULg; Leclercq, Yves ULg; Collette, Fabienne ULg et al

in Proceedings of the 8th bi-annual Meeting of the Belgian Society for Neuroscience (2009)

The neuropsychological profiles of patients with early Alzheimer’s disease (AD) appear to be heterogeneous. In this study, we examined whether this heterogeneity corresponds to the existence of ... [more ▼]

The neuropsychological profiles of patients with early Alzheimer’s disease (AD) appear to be heterogeneous. In this study, we examined whether this heterogeneity corresponds to the existence of cognitively distinct subtypes of AD or rather to impairments along a continuum of performances in different cognitive domains. A large group of 187 AD patients recruited in the European project NEST-DD performed a neuropsychological battery. A factor analysis of cognitive performance identified three factors, which respectively reflected attentional/instrumental function, declarative memory and executive function. Three clustering methods were applied on the factor scores in order to explore the existence of separate groups. The clustering methods indicated that cognitive profiles among the patients were sufficiently variable to identify clusters, but there was continuity between clusters rather than clear-cut subtypes. Moreover, clusters corresponded to various combinations of relatively impaired and preserved functions, suggesting multidimensional distribution within a large population of patients. Finally, clusters of cognitive profiles were characterized by different levels of metabolism in brain regions commonly (but variably) involved or relatively preserved in AD. [less ▲]

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See detailCombiner les mesures métaboliques cérébrales et neuropsychologiques permet une meilleure prédiction de la conversion vers une maladie d’Alzheimer chez les patients MCI
Bastin, Christine ULg; Adam, Stéphane ULg; LEKEU, Françoise ULg et al

in Revue Neurologique (2009), 165

Introduction. Une voie de recherche neurologique importante concerne la capacité de prédire sur base de l’évaluation initiale des patients avec Mild Cognitive Impairment (MCI) ceux qui vont développer une ... [more ▼]

Introduction. Une voie de recherche neurologique importante concerne la capacité de prédire sur base de l’évaluation initiale des patients avec Mild Cognitive Impairment (MCI) ceux qui vont développer une maladie d’Alzheimer (MA). Parmi les tests neuropsychologiques, le rappel indicé avec indiçage congruent lors de l’encodage et du rappel (RI48) apparaît comme le meilleur prédicteur du devenir des patients MCI (Ivanoiu et al., 2005). D’autre part, on a montré que les mesures métaboliques cérébrales (TEP-FDG), plus particulièrement l’hypométabolisme du cortex temporopariétal, prédit le déclin cognitif global dans le MCI mieux que des mesures neuropsychologiques (Chételat et al., 2005). Le but de notre étude était d’évaluer le pouvoir de prédiction pour la conversion du MCI vers une MA de deux prédicteurs robustes (performance au RI48 et métabolisme cérébral) pris soit isolément soit ensemble. Méthode. 50 patients MCI ont subi un examen en TEP-FDG au repos et ont réalisé le test de rappel indicé RI48 et le MMSE. Au terme d’un suivi neuropsychologique de 36 mois, 28 patients ont évolué vers une MA et 22 sont restés stables. Le métabolisme cérébral et les performances cognitives ont été comparés entre « convertisseurs » et MCI-stables. Des analyses discriminantes ont ensuite permis d’évaluer la capacité de classification de l’âge, du MMSE et des mesures métaboliques et mnésiques considérés individuellement ou selon diverses combinaisons. Résultat. Par comparaison avec les MCI-stables, les « convertisseurs » montraient un hypométabolisme du cortex temporal moyen bilatéralement, du cortex pariétal inférieur droit et du précuneus droit, et de plus faibles performances initiales au RI48. Prises individuellement, les différentes mesures permettaient le même taux de classification correcte (métabolisme cérébral = 76%, RI48 = 76%). L’âge et le MMSE étaient de faibles prédicteurs (exactitude de classification = 62% et 66% respectivement). Par contre, la combinaison des mesures métaboliques et des scores au RI48 prédisaient le mieux la progression vers la MA (88%). Conclusion. Les résultats suggèrent que la stratégie optimale pour identifier quels patients MCI ont plus de risque de développer une MA est de combiner les mesures métaboliques cérébrales et la performance à un test de mémoire très sensible. [less ▲]

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See detailMetabolism of no-carrier-added 2-[18F]fluoro-L-tyrosine in rats
Aerts, Joël ULg; Plenevaux, Alain ULg; Lemaire, Christian ULg et al

in BMC Medical Physics (2008), 8

Background: Several fluorine-18 labelled fluoroamino acids have been evaluated as tracers for the quantitative assessment of cerebral protein synthesis in vivo by positron emission tomography (PET). Among ... [more ▼]

Background: Several fluorine-18 labelled fluoroamino acids have been evaluated as tracers for the quantitative assessment of cerebral protein synthesis in vivo by positron emission tomography (PET). Among these, 2-[18F]fluoro-L-tyrosine (2-[18F]Tyr) has been studied in mice at a low specific activity. Its incorporation into proteins is fast and metabolism via other pathways is limited. The present in vivo study was carried out in normal awake rats using no-carrier-added 2-[18F]Tyr. Under normal physiological conditions, we have studied the incorporation into proteins and the metabolism of the tracer in different brain areas. Methods: No-carrier-added 2-[18F]Tyr was administered to awake rats equipped with chronic arterial and venous catheters. The time course of the plasma activity was studied by arterial blood sampling. The biodistribution of the activity in the main organs was studied at the end of the experiment. The distribution of radioactive species in plasma and brain regions was studied by acidic precipitation of the proteins and HPLC analysis of the supernatant. Results: The absolute uptake of radioactivity in brain regions was homogenous. In awake rats, nocarrier-added 2-[18F]Tyr exhibits a fast and almost quantitative incorporation into the proteins fractions of cerebellum and cortex. In striatum, this incorporation into proteins and the unchanged fraction of the tracer detected by HPLC could be lower than in other brain regions. Conclusion: This study confirms the potential of 2-[18F]fluoro-L-tyrosine as a tracer for the assessment of the rate of protein synthesis by positron emission tomography. The observed metabolism suggests a need for a correction for the appearance of metabolites, at least in plasma. [less ▲]

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See detailCyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies.
Lacan, Goran; Plenevaux, Alain ULg; Rubins, Daniel J. et al

in European Journal of Nuclear Medicine and Molecular Imaging (2008), 35(12), 2256-66

PURPOSE: Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperaz ine ([(18)F]MPPF) for ... [more ▼]

PURPOSE: Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperaz ine ([(18)F]MPPF) for binding to hydroxytryptamine(1A) (5-HT(1A)) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies. MATERIALS AND METHODS: Each Sprague-Dawley rat (n = 4) received a baseline [(18)F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.p.). Maximum a posteriori reconstructed images and volumetric ROIs were used to generate dynamic radioactivity concentration measurements for hippocampus, striatum, and cerebellum, with simplified reference tissue method (SRTM) analysis. Western blots were used to semiquantify P-gp regional distribution in brain. RESULTS: MicroPET studies showed that hippocampus uptake of [(18)F]MPPF was increased after cyclosporine; ex vivo studies showed similar increases in hippocampus and frontal cortex at 30 min, and for heart and kidney at 2.5 and 5 min, without concomitant increases in [(18)F]MPPF plasma concentration. P-gp content in cerebellum was twofold higher than in hippocampus or frontal cortex. CONCLUSIONS: These studies confirm and extend prior ex vivo results (J. Passchier, et al., Eur J Pharmacol, 2000) that showed [(18)F]MPPF as a substrate for P-gp. Our microPET results showed that P-gp modulation of [(18)F]MPPF binding to 5-HT(1A) receptors can be imaged in rat hippocampus. The heterogeneous brain distribution of P-gp appeared to invalidate the use of cerebellum as a nonspecific reference region for SRTM modeling. Regional quantitation of P-gp may be necessary for accurate PET assessment of 5-HT(1A) receptor density when based on tracer uptake sensitive to P-gp modulation. [less ▲]

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See detailLes corrélats métaboliques des processus contrôlés en mémoire dans la maladie d'Alzheimer très débutante
Bastin, Christine ULg; Kerrouche, Nacer; Lekeu, Françoise ULg et al

in Ergis, Anne-Marie; Fiori, N.; Chaby, L. (Eds.) et al Xème colloque international sur le vieillissement cognitif (2008)

Les processus contrôlés et automatiques de récupération mnésique ont été évalués au moyen de la Procédure de Dissociation des Processus appliquée à une tâche de complètement de trigrammes chez 59 patients ... [more ▼]

Les processus contrôlés et automatiques de récupération mnésique ont été évalués au moyen de la Procédure de Dissociation des Processus appliquée à une tâche de complètement de trigrammes chez 59 patients diagnostiqués comme « questionable Alzheimer’s disease » (QAD ou Mild Cognitive Impairment). Par ailleurs, le métabolisme cérébral du glucose des patients a été mesuré par FDG-PET. Comparativement à des volontaires âgés sains appariés, le profil mnésique des patients QAD était caractérisé par un déficit des processus contrôlés, mais une préservation des processus automatiques. Après un suivi de 30 mois, 27 des patients ont développé une maladie d’Alzheimer, tandis que 23 patients restèrent des QAD stables (9 sujets n’ont pas complété le suivi ou ont reçu un autre diagnostic au terme de celui-ci). Les deux sous-groupes présentaient le même degré de déclin des processus de mémoire contrôlés. Des corrélations cognitivo-métaboliques, ainsi qu’une analyse en composantes principales, ont permis de montrer que les corrélats métaboliques des processus contrôlés (à l’entrée dans l’étude) n’étaient les mêmes chez les patients qui allaient développer la maladie d’Alzheimer et chez les patients qui allaient rester stables. Chez les patients qui développaient ultérieurement une maladie d’Alzheimer, l’utilisation correcte des processus contrôlés était positivement corrélée à l’activité du cortex préfrontal dorsomédian, qui pourrait jouer un rôle dans les processus réflexifs de monitoring agissant sur les produits de la récupération. L’activité du cortex préfrontal dorsomédian était corrélée à l’activité métabolique des régions frontales bilatérales et du cortex cingulaire postérieur. Par contraste, chez les patients QAD stables, nous avons trouvé une corrélation avec la formation hippocampique antérieure, une région qui intervient dans la réactivation de l’épisode d’encodage des événements. [less ▲]

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See detailPET/CT of skull base meningiomas using 2-F-18-fluoro-L-tyrosine: Initial report
Rutten, Isabelle; Cabay, Jean-Evrard ULg; Withofs, Nadia ULg et al

in Journal of Nuclear Medicine (2007), 48(5), 720-725

Precise delineation of the shape of skull base meningiomas is critical for their treatment and follow-up but is often difficult using conventional imaging such as CT and MRI. We report our results with ... [more ▼]

Precise delineation of the shape of skull base meningiomas is critical for their treatment and follow-up but is often difficult using conventional imaging such as CT and MRI. We report our results with PET/CT and 2-(18)F-fluoro-L-tyrosine ((18)F-TYR), a marker of amino acid transport, as part of the yearly follow-up of irradiated patients. METHODS: Eleven patients (mean age, 56.5 y) with skull base meningiomas (n=13 lesions) previously irradiated were included. All patients received 300 MBq of (18)F-TYR and were imaged after 30 min of uptake, using a dedicated PET/CT system. The images were first visually examined, and regions of interest (ROI) were then placed over the transaxial PET slice showing the highest uptake. Another ROI was placed over the normal parietal cortex. Tumor-to-cortex activity ratios were obtained by dividing the maximum pixel value in the tumor ROI by the maximum pixel value in the cortex ROI. The PET/CT images were compared with the MR images obtained as part of routine follow-up. RESULTS: Accumulation of the tracer was higher in all meningiomas than in the surrounding tissue. The tumor-to-cortex activity ratio was 2.53 +/- 0.35 (range, 1.3-6). Nonneoplastic tissue such as hyperemic cavernous sinus did not take up the radionuclide and was therefore easily distinguished from the meningioma. The (18)F-TYR anomalies completely overlapped with the MR image in 54% of the tumors, extended beyond the MRI lesion in 38% of the tumors, and were smaller in 8% of the tumors. CONCLUSION: Meningiomas of the skull base are clearly visualized using (18)F-TYR PET/CT, even after irradiation. In addition to MRI, (18)F-TYR PET/CT images may contribute to the evaluation, delineation, and follow-up of these tumors. [less ▲]

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See detailAre spatial memories strengthened in the human hippocampus during slow wave sleep?
Peigneux, Philippe ULg; Laureys, Steven ULg; Fuchs, Sonia et al

in Neuron (2004), 44(3), 535-545

In rats, the firing sequences observed in hippocampal ensembles during spatial learning are replayed during subsequent sleep, suggesting a role for posttraining sleep periods in the offline processing of ... [more ▼]

In rats, the firing sequences observed in hippocampal ensembles during spatial learning are replayed during subsequent sleep, suggesting a role for posttraining sleep periods in the offline processing of spatial memories. Here, using regional cerebral blood flow measurements, we show that, in humans, hippocampal areas that are activated during route learning in a virtual town are likewise activated during subsequent slow wave sleep. Most importantly, we found that the amount of hippocampal activity expressed during slow wave sleep positively correlates with the improvement of performance in route retrieval on the next day. These findings suggest that learning-dependent modulation in hippocampal activity during human sleep reflects the offline processing of recent episodic and spatial memory traces, which eventually leads to the plastic changes underlying the subsequent improvement in performance. [less ▲]

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See detailHighly enantioselective synthesis of no-carrier-added 6-[18F]Fluoro-L-dopa by chiral phase-transfer alkylation
Lemaire, Christian ULg; Gillet, Steve; Guillouet, Stéphane et al

in European Journal of Organic Chemistry (2004), (13), 2899-2904

[F-18]Fluoro-L-dopa, an important radiopharmaceutical for positron emission tomography (PET), has been synthesized using a phase-transfer alkylation reaction. A chiral quaternary ammonium salt derived ... [more ▼]

[F-18]Fluoro-L-dopa, an important radiopharmaceutical for positron emission tomography (PET), has been synthesized using a phase-transfer alkylation reaction. A chiral quaternary ammonium salt derived from a Cinchona alkaloid served as phase-transfer catalyst for the enantioselective alkylation of a glycine derivative. The active methylene group of this Schiff-base substrate was deprotonated with cesium hydroxide and rapidly alkylated by the 2-[F-18]fluoro-4,5-dimethoxybenzyl halide (X = Br, I). The reaction proceeded with high yield (> 90%) at 0 degreesC or room temperature in various solvents such as toluene or dichloromethane. Preparation of the [F-18]alkylating agent on a solid support was developed. After labelling, the labeled [F-18]fluoroveratraldehyde was trapped on a (t)C18 cartridge and then converted on the cartridge into the corresponding benzyl halide derivatives by addition of aqueous sodium borohydride and gaseous hydrobromic or -iodic acid. Hydrolysis and purification by preparative HPLC made 6-[F-18]fluoro-L-dopa ready for human injection in a 25-30% decay-corrected radiochemical yield in a synthesis time of 100 min. The product was found to be chemically, radiochemically and enantiomerically pure (ee > 95%). (C) Wiley-VCH Verlag GmbH [less ▲]

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See detailImaging a cognitive model of apraxia: The neural substrate of gesture-specific cognitive processes
Peigneux, Philippe ULg; Van der Linden, Martial ULg; Garraux, Gaëtan ULg et al

in Human Brain Mapping (2004), 21(3), 119-142

The present study aimed to ascertain the neuroanatomical basis of an influential neuropsychological model for upper limb apraxia [Rothi LJ, et al. The Neuropsychology of Action. 1997. Hove, UK: Psychology ... [more ▼]

The present study aimed to ascertain the neuroanatomical basis of an influential neuropsychological model for upper limb apraxia [Rothi LJ, et al. The Neuropsychology of Action. 1997. Hove, UK: Psychology Press]. Regional cerebral blood flow was measured in healthy volunteers using (H2O)-O-15 PET during performance of four tasks commonly used for testing upper limb apraxia, i.e., pantomime of familiar gestures on verbal command, imitation of familiar gestures, imitation of novel gestures, and an action-semantic task that consisted in matching objects for functional use. We also re-analysed data from a previous PET study in which we investigated the neural basis. of the visual analysis of gestures. First; we found that two sets of discrete brain areas are predominantly engaged in the imitation of familiar and novel gestures, respectively. Segregated brain activation for novel gesture mutation concur with neuropsychological reports to support the hypothesis that knowledge about the organization of the human body mediates the transition from visual perception to motor execution when imitating novel gestures [Goldenberg Neuropsychologia 1995;35.63-72]. Second, conjunction analyses revealed distinctive neural bases for most of the gesture-specific cognitive processes proposed in this cognitive model of upper limb apraxia. However, a functional analysis of brain imaging data suggested that one single memory store may be used for "to be-perceived" and "to-be-produced" gestural representations, departing from Rothi et al.'s proposal. Based on the above considerations, we suggest and discuss a revised model for upper limb apraxia that might best account for both brain imaging findings and neuropsychological dissociations reported in the apraxia literature. (C) 2004 Wiley-Liss, Inc. [less ▲]

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See detailLearned material content and acquisition level modulate cerebral reactivation during posttraining rapid-eye-movements sleep
Peigneux, Philippe ULg; Laureys, Steven ULg; Fuchs, Sonia et al

in NeuroImage (2003), 20(1), 125-134

We have previously shown that several brain areas are activated both during sequence learning at wake and during subsequent rapid-eye-movements (REM) sleep (Nat. Neurosci. 3 (2000) 831-836), suggesting ... [more ▼]

We have previously shown that several brain areas are activated both during sequence learning at wake and during subsequent rapid-eye-movements (REM) sleep (Nat. Neurosci. 3 (2000) 831-836), suggesting that REM sleep participates in the reprocessing of recent memory traces in humans. However, the nature of the reprocessed information remains open. Here, we show that regional cerebral reactivation during posttraining REM sleep is not merely related to the acquisition of basic visuomotor skills during prior practice of the serial reaction time task, but rather to the implicit acquisition of the probabilistic rules that defined stimulus sequences. Moreover, functional connections between the reactivated cuneus and the striatum-the latter being critical for implicit sequence learning-are reinforced during REM sleep after practice on a probabilistic rather than on a random sequence of stimuli. Our results therefore support the hypothesis that REM sleep is deeply involved in the reprocessing and optimization of the high-order information contained in the material to be learned. In addition, we show that the level of acquisition of probabilistic rules attained prior to sleep is correlated to the increase in regional cerebral blood flow during subsequent REM sleep. This suggests that posttraining cerebral reactivation is modulated by the strength of the memory traces developed during the learning episode. Our data provide the first experimental evidence for a link between behavioral performance and cerebral reactivation during REM sleep. (C) 2003 Elsevier Inc. All rights reserved. [less ▲]

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See detailWhole-body tumor imaging using PET and 2-F-18-fluoro-L-tyrosine : Preliminary evaluation and comparison with F-18-FDG
Hustinx, Roland ULg; Lemaire, Christian ULg; Jerusalem, Guy ULg et al

in Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine (2003), 44(4), 533-539

18F-FDG PET imaging is now established as a valuable tool for evaluating cancer patients. However, a limitation of 18F-FDG is its absence of specificity for tumor. Both protein synthesis and amino acid ... [more ▼]

18F-FDG PET imaging is now established as a valuable tool for evaluating cancer patients. However, a limitation of 18F-FDG is its absence of specificity for tumor. Both protein synthesis and amino acid transport are enhanced in most tumor cells, but their metabolism is less affected in inflammation. We therefore decided to evaluate the ability of PET with 2-18F-fluoro-L-tyrosine (18F-TYR) to visualize cancer lesions in patients compared with 18F-FDG PET. Methods: 18F-FDG PET and 18F-TYR PET were performed on 23 patients with histologically proven malignancies (11 non-small cell lung cancers (NSCLCs), 10 lymphomas, and 2 head and neck carcinomas). Fully corrected, whole-body PET studies were obtained on separate days. 18F-FDG studies were performed after routine clinical fashion. 18F-TYR studies were started 36 ± 6 min after tracer injection and a second scan centered over a reference lesion was acquired after completion of the whole-body survey-on average, 87 min after injection. Standardized uptake values (SUVs) were calculated for all abnormal foci and for various normal structures. Results were compared with pathologic or correlative studies. Results: 18F-FDG PET correctly identified 54 malignant lesions, among which 36 were also visualized with 18F-TYR (67%). 18F-TYR did not detect any additional lesion. Tumor SUVs (SUVbw, 5.2 vs. 2.5), tumor-to-muscle (7.4 vs. 2.7), and tumor-to-mediastinum activity ratios (3 vs. 1.4) were higher with 18F-FDG than with 18F-TYR. Two of 11 NSCLCs and 4 of 10 lymphomas were understaged with 18F-TYR compared with 18F-FDG. Although the NSCLC lesions missed by 18F-TYR PET were small, several large lymphoma lesions did not accumulate the tracer. In 4 patients, 18F-TYR-positive lesions coexisted with 18F-TYR-negative lesions. There was a high physiologic 18F-TYR uptake by the pancreas (average SUVbw, 10.3) and the liver (average SUVbw, 6.3). Muscle and bone marrow uptakes were also higher with 18F-TYR than with 18F-FDG: average SUVbw, 1 versus 0.7 and 2.6 versus 1.8, respectively. There was no change over time in the 18F-TYR uptake by the tumors or the normal structures. Conclusion: 18F-TYR PET is not superior to 18F-FDG PET for staging patients with NSCLC and lymphomas. [less ▲]

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See detailBrain function in the vegetative state
Laureys, Steven ULg; Antoine, S.; Boly, Mélanie ULg et al

in Acta Neurologica Belgica (2002), 102(4), 177-185

Positron emission tomography (PET) techniques represent a useful tool to better understand the residual brain function in vegetative state patients. It has been shown that overall cerebral metabolic rates ... [more ▼]

Positron emission tomography (PET) techniques represent a useful tool to better understand the residual brain function in vegetative state patients. It has been shown that overall cerebral metabolic rates for glucose are massively reduced in this condition. However, the recovery of consciousness from vegetative state is not always associated with substantial changes in global metabolism. This finding led us to hypothesize that some vegetative patients are unconscious not just because of a global loss of neuronal function, but rather due to an altered activity in some critical brain regions and to the abolished functional connections between them. We used voxel-based Statistical Parametric Mapping (SPM) approaches to characterize the functional neuroanatomy of the vegetative state. The most dysfunctional brain regions were bilateral frontal and parieto-temporal associative cortices. Despite the metabolic impairment, external stimulation still induced a significant neuronal activation (i.e., change in blood flow) in vegetative patients as shown by both auditory click stimuli and noxious somatosensory stimuli. However this activation was limited to primary cortices and dissociated from higher-order associative cortices, thought to be necessary for conscious perception. Finally, we demonstrated that vegetative patients have impaired functional connections between distant cortical areas and between the thalami and the cortex and, more importantly, that recovery of consciousness is paralleled by a restoration of this cortico-thalamo-cortical interaction. [less ▲]

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